Intellectual disability is a prevalent developmental disorder, affecting 1-3% of the population. Advances in genetics have led to the identification of many intellectual disability proteins. However, how these proteins regulate brain development and the mechanisms by which mutations of these proteins cause intellectual disability remain poorly understood. During the past few years, we have characterized the functions of specific nuclear X-linked intellectual disability (XLID) proteins in brain development. Mutations of the XLID protein PHF6 cause the Brjeson-Forssman-Lehmannsyndrome (BFLS), which features intellectual delay and epilepsy. We have discovered that knockdown of PHF6 profoundly impairs neuronal migration in the mouse cerebral cortex in vivo. Remarkably, PHF6 physically associates with the PAF1 transcription elongation complex, and inhibition of PAF1 phenocopies the PHF6 knockdown-induced migration phenotype in vivo. These findings define PHF6 and the PAF1 complex as components of a novel transcriptional pathway that drives neuronal migration in the brain. Our findings have also raised fundamental questions on the mechanisms of the PHF6/PAF1 transcriptional pathway in neuronal migration and on the pathophysiological relevance of this pathway in intellectual disability. To address these questions, we will first perform structure- function analyses of PHF6 in neuronal migration in the mouse cerebral cortex. We will test the effect of BFLS patient-specific mutations of PHF6 on PHF6-dependent transcription and neuronal migration. We will also test the hypothesis that phosphorylation of PHF6 on specific sites regulates PHF6-dependent transcription and neuronal migration. In other studies, we will test the hypothesis that PHF6 regulates transcription elongation of actively transcribed genes in neurons and identify targets of PHF6 that drive neuronal migration. Finally, we will determine the effect of deregulation of the PHF6/PAF1 transcriptional pathway during cortical development on the formation of white matter heterotopias and neuronal excitability in postnatal mice. The proposed research will advance our understanding of the transcriptional mechanisms that govern neuronal positioning in the brain as well as lead to insights into how deregulation of these mechanisms contributes to the pathogenesis of intellectual disability. These studies also hold the potential of laying the foundation for novel therapeutic approaches to the treatment of BFLS and developmental cognitive disorders.